Coccidioidomycosis is a regional fungal disease in desert areas of the Southwestern U.S. and is of particular importance to Arizona and California. The importance of this disease extends beyond the endemic areas due to extensive travel to these locations. Infection with Coccidioides spp. may cause illness ranging from a mild, self-limiting, pulmonary syndrome to serious or life-threatening disease. The later is more likely in patients with compromised immunity as seen following organ transplant, cancer chemotherapy, or AIDS. Complications are also seen in certain racial groups (African American and Filipino), pregnancy, and in patients receiving drugs that suppress immune function (corticosteroids, TNF antagonists). Nikkomycin Z has been declared an orphan drug by the FDA and is eligible for fast track review. In animal models, nikkomycin Z has shown potential to eradicate the fungus from lung lesions which is not seen with existing antifungal drugs. NikZ is absorbed after oral administration and was well tolerated and safe based on a single dose study completed in man. The goal of this proposal is to support further development of NikZ and complement plans for a Phase I/II study in patients with coccidioidal pneumonia. The aims of this proposal include: conduct of PK/PD studies in mice with experimental coccidioidomycosis, establishment of a GLP complient analytical laboratory and development of optimized analytical methods, and conduct of additional preclinical studies needed to support continued clinical studies. Simultaneous, planning for the next clincial study (Phase I/II) will be ongoing with support from an NIH R34 planning grant. The PK/PD studies are needed to determine the most effective dose strategy. The results can be extrapolated to humans and guided by exposure targets in mice in relation to human pharmacokinetics and existing single dose safety results. NikZ has stability problems in biological fluids and further assay development is needed before future human studies are performed to define handling procedures and ensure reliability given limitations in clinical settings. Moreover, a GLP facility will be needed and will serve as a core laboratory for all studies ongoing with NikZ. The FDA is requiring drug metabolism/drug interaction screening before any treatment studies are initiated, and screening for cardiac ion channel effects is also needed. The planned studies will pave the way for continued development. Project Narrative: Coccidioidomycosis (Valley Fever) is a fungal infection occurring in the southwestern U.S. and affecting residents as well as visitors. Although most affected people develop only mild symptoms that resolve without treatment, some will develop prolonged and sometimes serious illness. Currently available therapies do not fully control this disease, thus our goal is to further study a new drug that represents a promising new therapy for Valley Fever.